4-Acylaminophenylacetamidines and a method for their preparation

ABSTRACT

New 4-acylaminophenylacetamidines of the formula: ##SPC1## 
     In which R is a straight or branched chain alkoxyalkyl having 3 to 8 carbon atoms or straight or branched chain alkenyloxyalkyl having 3 to 8 carbon atoms wherein the alkoxy moiety or alkenyloxy moiety may substituted by alkoxy or phenyl, and including the non-toxic pharmacologically acceptable salts thereof. The products have utility as parasiticides. 
     The products are obtained by either of two methods: (1) via the reaction of an N&#39;-(4-aminophenyl)-N,N-dimethylacetamidine with an acylating agent or (2) via the reaction of a 4-acylaminoaniline with an N,N-dimethylacetamide or N,N-dimethylthioacetamide.

This invention relates to new 4-phenyl-acetamidines and to a method fortheir preparation. The products have utility as parasiticides.

It is stated in German Published Specification No. 2,029,299 thatN'-phenyl-N,N-dimethylacetamidines are active against helminths. Howeverthese compounds exhibit a relatively low therapeutic index.

This invention describes novel products which also exhibit anthelminticactivity, particularly parasiticidal activity and which possess animproved therapeutic index.

The novel products of this invention are 4-acylaminophenylacetamidinesof the following formula: ##SPC2##

Wherein

R is straight or branched chain alkoxyalkyl having 3 to 8 carbon atomsunsubstituted or substituted by 1 or 2 of the same or different membersselected from the group consisting of alkoxy and phenyl; or straight orbranched chain alkenyloxyalkyl having 3 to 8 carbon atoms unsubstitutedor substituted by 1 or 2 of the same or different members selected fromthe group consisting of alkoxy and phenyl;

And the non-toxic pharmacologically acceptable salts thereof. Theseproducts combine a strong parasiticidal effect with a very goodtherapeutic index.

One embodiment of this invention comprises the following4-acylaminophenylacetamidines: ##SPC3##

Wherein

R is straight or branched chain alkoxyalkyl having 3 to 8 carbon atoms,either unsubstituted or substituted in the alkoxy moiety by one or twoof the same or different members selected from the group consisting ofalkoxy of 1 to 4 carbon atoms and phenyl; or straight or branched chainalkenyloxyalkyl having 3 to 8 carbon atoms, either unsubstituted orsubstituted in the alkoxy moiety by one or two of the same or differentmembers selected from the group consisting of alkoxy of 1 to 4 carbonatoms and phenyl;

And the non-toxic pharmacologically acceptable salts thereof.

A second embodiment of this invention relates to those4-acylaminophenylacetamidines of the following formula: ##SPC4##

Wherein

R is straight or branched chain alkoxyalkyl having 3 to 8 carbon atoms,either unsubstituted or substituted in the alkoxy moiety by one or twoof the same or different members selected from the group consisting ofalkoxy of 1 or 2 carbon atoms and phenyl; or straight or branched chainalkenyloxyalkyl having 3 to 8 carbon atoms, either unsubstituted orsubstituted in the alkoxy moiety by one or two of the same or differentmembers selected from the group consisting of alkoxy of 1 or 2 carbonatoms and phenyl;

And the non-toxic pharmacologically acceptable salts thereof.

A preferred embodiment of this invention relates to4-acylaminophenylacetamidines of the following formula: ##SPC5##

wherein

R is ethoxymethyl, propoxymethyl, butoxymethyl, isobutoxymethyl,isopropoxymethyl, t.-butoxymethyl, amyloxymethyl, isoamyloxymethyl,α-methoxypropyl, β-methoxypropyl, α-ethoxypropyl, β-ethoxypropyl,α-propoxypropyl, β-propoxypropyl, α-isopropoxypropyl,β-isopropoxypropyl, α-methoxybutyl, β-methoxybutyl, γ-methoxybutyl,α-ethoxybutyl, β-ethoxybutyl, γ-ethoxybutyl, allyloxymethyl,crotyloxymethyl, α-allyloxypropyl, β-allyloxypropyl, α-crotyloxypropyl,β-crotyloxypropyl, benzyloxymethyl, α-benzyloxypropyl,β-benzyloxypropyl, methoxyethoxymethyl or ethoxyethoxymethyl;

and the non-toxic pharmacologically acceptable salts thereof.

The following products are illustrative of the4-acylaminophenylacetamidines of this invention:

N'-(ethoxyacetylaminophenyl)-N,N-dimethylacetamidine and itshydrochloride,

N'-(propyloxyacetylaminophenyl)-N,N-dimethylacetamidine and itshydrochloride,

N'-(i-propyloxyacetylaminophenyl)-N,N-dimethylacetamidine and itshydrochloride,

N'-(butyloxyacetylaminophenyl)-N,N-dimethylacetamidine and itshydrochloride,

N'-(i-butyloxyacetylaminophenyl)-N,N-dimethylacetamidine and itshydrochloride,

N'-(methoxymethylacetylaminophenyl)-N,N-dimethylacetamidine and itshydrochloride,

N'-(methoxypropionylaminophenyl)-N,N-dimethylacetamidine and itshydrochloride,

N'-(ethoxypropionylaminophenyl)-N,N-dimethylacetamidine and itshydrochloride,

N'-(α-methylpropyloxyacetylaminophenyl)-N,N-dimethylacetamidine and itshydrochloride,

N'-(γ,γ-dimethylpropyloxyacetylaminophenyl)-N,N-dimethylacetamidine andits hydrochloride,

N'-(allyloxyacetylaminophenyl)-N,N-dimethylacetamidine and

N'-(crotyloxyacetylaminophenyl)-N,N-dimethylacetamidine.

The 4-acylaminophenylacetamidines of this invention are substantiallyless toxic and approximately as active against hookworm of dogs,Ancylostoma caninum when compared against the known productN'-(4-aminophenyl)-N,N-dimethylacetamidine. Thus, for example, whencompared against the known productN'-(methoxyacetylaminophenyl)-N,N-dimethylacetamidine, the products ofthis invention exhibit a substantially better parasiticidal effect and amore advantageous therapeutic index. This improvement in the therapeuticindex for the instant products is of particular advantage in thetreatment of helminthiases in animals.

The products (I) of this invention are obtained by either of twomethods.

a. One such method consists of treating an aminophenylacetamidine of theformula: ##SPC6##

with the acylating agent:

    R--CO--Z                                                   (III)

wherein

Z is a carbonyl-activating radical which can be easily split off; and

R is as defined above.

Illustrative of the carbonyl-activating radicals within the definitionof Z are, for example, halo, preferably chloro and bromo, anhydride,hydroxy, or alkoxy, alkenyloxy and aryloxy which may optionally besubstituted in conducting this process. When the aminophenylacetamidinereactant (II) is treated with the acylating agent an acid bindingreagent is generally used when Z in the acylating agent representshydroxy; alternatively, when the acylating agent is other than hydroxy,a condensation agent, that is, a dehydrating agent, is generallyemployed. Illustrative of suitable acid binding agents are, for example,organic and inorganic bases such as sodium and potassium hydroxides,sodium bicarbonate, potassium carbonate, triethylamine and pyridine.Preferred condensation agents which may be employed in this processinclude, for example, inorganic acid halides such as phosphorusoxychloride, or phosphorous trichloride, thionyl chloride, phosgene,boron, trifluoride, a dialkyl sulphate such as dimethyl sulphate ordiethyl sulphate, and organic acid halides such as benzoyl chloride andp-toluenesulphonic acid chloride. The following equation illustratesthis method of preparation; however, it is to be understood that theethoxyacetylchloride and N'-(4-aminophenyl)-N,N-dimethylacetamide whichare used as starting materials in the following equation areillustrative only and, in practice, any aminophenylacetamidine andacylating agent falling within the scope of formulae II and III, supra,can be substituted therefor in an otherwise similar process to affordthe instant products (I): ##SPC7##

b. A second method for preparing the instant products (I) consists intreating an acylaminoaniline of the formula: ##SPC8##

wherein R is as defined above, with N,N-dimethylacetamide,N,N-dimethylthioacetamide or a functional derivative ofN,N-dimethylacetamide. This process is preferably conducted in thepresence of a condensation agent. Preferred condensation agents include,for example, inorganic acid halides such as phosphorus oxychloride,phosphorus trichloride, thionyl chloride, phosgene, boron, trifluoride,a dialkyl sulphate such as dimethyl sulphate or diethyl sulphate, andorganic acid halides such as benzoyl chloride and p-toluenesulphonicacid chloride. Also, when N,N-dimethylthioacetamide itself is employed,mercury containing condensation agents such as mercuric oxide arepreferably used. The following equation illustrates this method ofpreparation; however, it is to be understood that the4-ethoxyacetylaminoaniline and N,N-dimethylacetamide which are employedas starting materials in the following equation are merely illustrativeof the reactants which may be utilized and, in practice, any reactantsfalling within the scope of formula (IV), supra, is to be considered asbeing within the scope of this invention: ##SPC9##

As indicated above, various functional derivatives of theN,N-dimethylacetamide depicted in the foregoing equation may be utilizedin this process. Typical of these functional derivatives are, inaddition to N,N-dimethylthioacetamide, the following:N,N-dimethylthioacetamide, N,N-dimethylacetamide-dialkylacetals,N,N-dimethylthioacetamide-dialkylacetals,1-dimethylamino-1-alkoxy-ethylene and1-dimethylamino-1-alkylmercapto-ethylene.

Both of the foregoing methods for preparing the instant products employsimilar reaction conditions. Both processes can be carried out in thepresence of an inert diluent such as an aromatic hydrocarbon, as, forexample, benzene, toluene or xylene, or, alternatively, chlorinatedhydrocarbons may be used as, for example, chlorobenzene, dichlorobenzeneand tetrachloroethylene.

The reaction temperatures in both processes can be varied over a widerange but, in general, the reaction is conducted at a temperature ofbetween about 10° and 130°C, preferably, at between about 20° and 120°C.

The proportions in which the starting materials are combined is notparticularly critical to either of the instant processes and, ingeneral, the reactants are usually combined in approximately equimolaramounts. In addition, the acylating agents and dehydrating agentsemployed in these processes are also used in equimolar quantities.

In practice, both of the instant processes are effected by simplycombining the reactants either in the presence or absence of a solvent.Thereafter, the reaction mixture is preferably heated as, for example,at temperatures of 80° to 120°C. The resulting products can then beisolated by pouring the reaction mixture into water, separating out thedesired product, drying and then recrystallizing or distilling the finalproduct.

The good anti-parasitic activity and low toxicity of the instantproducts (I) is believed to be attributed to their ability to maintain arelatively stable level in the blood, generally, at a concentration ofbetween about 4 and 8 γ/ml.

In particular, the products of this invention exhibit a surprisinglygood and broad range of effectiveness against the following helminths,that is, nematodes and cestodes:

I. Nematodes

1. Ancylostoma caninum, Uncinaria stenocephala and Bunostomumtrigonocephalum (hookworms) from the family of the Ancylostomatidae;

2. Haemonchus contortus, Trichostrongylus colubriformis, Cooperiapunctata, Ostertagia circumcincta, Nippostrongylus muris andNematospiroides dubius (stomach worms and worms of the small intestine)from the family of the Trichostrongylidae;

3. Oesophagostomum columbianum and Chabertia ovina (worms of the largeintestine) from the family of the Strongylidae;

4. Strongyloides ratti (dwarf threadworms) from the family of theRhabditidae;

5. Toxocara canis, Toxascaris leonina and Ascaris suum larvae (mawworms) from the familae of the Ascaridae or Anisakidae;

6. Aspiculuris tetraptera (pin-worms) from the family of the Oxyuridae;

7. Heterakis spumosa from the family of the Heterakidae.

II. Cestodes

1. Hymenolepis nana and Hymenolepis microstoma (tapeworms) from thesuperfamily of the Taenioidea.

This activity is illustrated by the following results.

Hookworm Test in Dog

Dogs experimentally infected with Ancylostoma caninum were treated afterthe expiration of the pre-patency period of the parasites.

The active compound (I) was administered orally in the amount indicatedas pure active compound or as a 10% strength solution in lactic acid ingelatine capsules.

The degree of effectiveness was determined by counting the wormsexpelled after the treatment and the worms remaining in the test animal,after dissection, and calculating the percentage of the worms expelled.

Table 1 below compares the maximum dose in mg/kg survived by mice afterperoral administration (column I) with the dose, in mg/kg, at which,after peroral administration, 90% of all worms have been expelled(column II). ##EQU1##

From the foregoing data, it is apparent that the compounds of thisinvention are, in general, less toxic than closely related knownproducts and, in addition, are approximately equally active againsthookworm of dogs, Ancylostoma caninum but substantially more effectivethan the closely related R methoxymethyl compounds. The compounds of thepresent invention thus have a more desirable therapeutic index. Thesmaller concentration which need be employed for the instant products ascompared to the known compounds offers particular advantages in thetreatment of helminthiases since it is then possible to formulate acomposition which is more easily administered.

The compounds (I) of this invention can be utilized as the activeingredient in anthelmintic compositions having utility in veterinarymedicine. These compositions contain a major or minor amount of at leastone compound (I) of this invention as, for example, from about 99.5 to0.1%, preferably 95 to 0.5%, and most preferably from about 0.5 to 90%of the compound (I) in combination with a pharmaceutically acceptablenon-toxic inert diluent or carrier. The diluent or carrier comprises oneor more solid, semi-solid or liquid medium, filler or formulationadjuvant which is non-toxic, inert and pharmaceutically acceptable.Also, the instant compositions are preferably in dosage unit form; i.e.,in physically discrete units containing a predetermined amount of thedrug corresponding to a fraction or multiple of the dose which iscalculated to produce the desired therapeutic response. The dosage unitscan contain one, two, three, four or more single doses or,alternatively, one-half, one-third or one-fourth of a single dose. Asingle dose preferably contains an amount sufficient to produce thedesired therapeutic effect upon administration at one application of oneor more dosage units according to a predetermined dosage regimen,usually a whole, half, third or quarter of the daily dosage administeredonce, twice, three or four times a day. Other therapeutic agents canalso be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, it is generally advantageous toadminister amounts of from about 0.1 to 50 mg of the compound (I) per kgof body weight per day. In some instances a sufficient therapeuticeffect can be obtained at a lower dose while in others, a larger dosewill be required. A preferred daily dosage is in the range of from about50 mg to 5 g of the active ingredient (I).

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions, ampoules or suppositories, and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl, cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

The diluents to be used in pharmaceutical compositions for formulationinto tablets, dragees, capsules and pills include the following: (a)fillers and extenders: starch, sugars, mannitol, and silicic acid; (b)binding agents: carboxymethyl cellulose and other cellulose derivatives,alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents:glycerol; (d) disintegrating agents: agar-agar, calcium carbonate andsodium bicarbonate; (d) agents for retarding dissolution: paraffin; (f)resorption accelerators: quaternary ammonium compounds; (g) surfaceactive agents: cetyl alcohol and glycerol monostearate; (h) adsorptivecarriers: kaolin and bentonite; (i) lubricants: talc, calcium andmagnesium stearate and solid polyethylene glycols.

The tablets, dragees, capsules and pills formed from the pharmaceuticalcompositions of the invention can have the customary coatings, envelopesand protective matrices, which may contain opacifiers. They can beconstituted as a timed release or sustained release formulation so thatthey release only the active ingredient or, preferably, release theactive ingredient in a particular part of the intestinal tract, possiblyover a period of time. Thus, for example, the coatings, envelopes andprotective matrices may be made, of polymeric substances or waxes.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a non-toxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low melting water soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher esters as forexample myristyl palmitate, or mixtures thereof.

Topical administration can be effected utilizing solid dosage unit formssuch as powders or liquid or semi-liquid dosage unit forms such assolutions, suspensions, ointments, pastes, creams and gels. The powdersare formulated utilizing such carrriers as talc, bentonite, silicicacid, polyamide powder, animal and vegetable fats, waxes, paraffins,starch, tragacanth, cellulose derivatives, polyethylene glycols,silicones, talc and zinc oxide or mixtures of these substances. Liquidand semiliquid formulations can utilize such carriers, in addition tothose described above, as polyethylene glycol, vegetable and mineraloils, alcohols such as isopropanol and the like. Other excipients suchas emulsifiers, preservatives, colorants, perfumes and the like can alsobe present.

Formulations can also be administered as an aerosol, utilizing the usualpropellants such as the chlorofluorohydrocarbons. The pharmaceuticalcompositions which are sprays can also contain the usual diluents, e.g.lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, andpolyamide powder or mixtures of these substances. Aerosol sprays can,for example, contain the usual propellants, e.g.chlorofluorohydrocarbons.

The following examples are illustrative of the products (I) of thisinvention and the methods for their preparation.

EXAMPLE 1 ##SPC10##

N'-(4-Aminophenyl)-N,N-dimethylacetamidine (212 g.) is dissolved in 500ml of methylene chloride and added dropwise at 5°C to a solution of 161g of ethoxyacetyl chloride in 500 ml of methylene chloride. The mixtureis stirred for 30 minutes and evaporated in vacuo. The residue is thenrecrystallized from a mixture of ethyl acetate and alcohol and afterfiltration 326 g of N'-(ethoxyacetylaminophenyl)-N,N-dimethylacetamidinehydrochloride, melting point 186° - 187°C are obtained. The free base isobtained by addition of sodium hydroxide solution to afford the desiredproduct having a boiling point of 192° - 194°C (0.1 mm Hg.).

By following the above procedure but substituting the appropriateacylating agent for the ethoxyacetyl chloride described therein, thefollowing products are obtained. ##EQU2##

EXAMPLE 2

17.7 g of N'-(4-aminophenyl)-N,N-dimethylacetamidine in 50 ml ofethoxyacetic anhydride are heated to 100°C and evaporated in vacuo. Theresidue is rendered alkaline with sodium hydroxide solution and theorganic phase is taken up in a mixture of chloroform/ether, and upondistillation in a vacuum, 22.5 g ofN'-(4-ethoxyacetylaminophenyl)-N,N-dimethylacetamidine, boiling point(0.1 mm Hg) 192°-194°C is obtained.

EXAMPLE 3

79.5 g of phosphorus oxychloride is added dropwise at 20°C to 93.2 g ofN,N-dimethylacetamide dissolved in 1,000 ml of toluene. The mixture isstirred for 3 hours at 20°C, whereafter 97 g of4-ethoxyacetylaminoaniline is added and the resulting mixture is stirredovernight at 20°C and subsequently heated to 100°C for 1 hour. Afterdecanting the toluene, the residue is taken up in a mixture of water andchloroform. Sodium hydroxide solution is then added with cooling and theorganic phase is separated off. Upon distillation in vacuo 43 g ofN'-(4-ethoxyacetylaminophenyl)-N,N-dimethylamidine, boiling point (0.1mm Hg) 192° - 194°C, is obtained.

Upon substituting phosgene or para-toluenesulphonic acid chloride ordimethyl sulphate for the phosphorous oxychloride condensation agent, anidentical product is obtained.

EXAMPLE 4

185 g of mercury oxide is added to a solution of 51.5 g ofN,N-dimethylthioacetamide and 80 g of 4-ethoxyacetylaminoaniline in 500ml of ethanol and the mixture is vigorously stirred for 8 hours at 0°Cand then for 15 hours at 80°C. The precipitate is filtered off, theresidue is distilled in vacuo and 18.6 g ofN'-(ethoxyacetylaminophenyl)-N,N-dimethylacetamidine, boiling point (0.1mm Hg) 192° - 194°C, is obtained.

EXAMPLE 5

19.4 g of 4-ethoxyacetylaminoaniline and 30 g ofN,N-dimethylacetamide-diethylacetal are gradually heated to 80° - 100°Cuntil the theoretical amount of alcohol has been split off. Upondistillation of the reaction product, 21 g ofN'-(4-ethoxyacetylaminophenyl)-N,N-dimethylacetamidine, boiling point(0.1 mm Hg) 192° - 194°C, is obtained.

An identical product is obtained if, instead ofN,N-dimethylacetamide-diethylacetal, the following reactants are used:1-dimethylamino-1-ethoxyethylene, 1-dimethylamino-1-methoxyethylene,N,N-dimethylacetamide-dimethylacetal orN,N-dimethylthioacetamide-S,S-dimethylacetal.

What is claimed is:
 1. A compound of the formula: ##SPC11##or apharmaceutically acceptable non-toxic salt thereof wherein R is straightor branched chain alkoxyalkyl having 3 to 8 carbon atoms, eitherunsubstituted or substituted in the alkoxy moiety by one or two of thesame or different members selected from the group consisting of alkoxyof 1 to 4 carbon atoms and phenyl; or straight or branched chainalkenyloxyalkyl having 3 to 8 carbon atoms either unsubstituted orsubstituted in the alkoxy moiety by one or two of the same or differentmembers selected from the group consisting of alkoxy of 1 to 4 carbonatoms and phenyl.
 2. A compound according to claim 1wherein R isstraight or branched chain alkoxyalkyl having 3 to 8 carbon atoms,either unsubstituted or substituted in the alkoxy moiety by one or twoof the same or different members selected from the group consisting ofalkoxy of 1 or 2 carbon atoms and phenyl; or straight or branched chainalkenyloxyalkyl having 3 to 8 carbon atoms, either unsubstituted orsubstituted in the alkoxy moiety by one or two of the same or differentmembers selected from the group consisting of alkoxy of 1 or 2 carbonatoms and phenyl.
 3. A compound according to claim 1wherein R isethoxymethyl, propoxymethyl, butoxymethyl, isopropoxymethyl,isobutoxymethyl, sec.-butoxymethyl, isoamyloxymethyl, α-methoxyethyl,α-ethoxyethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl,benzyloxyethyl, benzyloxymethyl, allyloxymethyl, 2-isobutenyloxymethyl,2-butenyloxymethyl, (2-methoxyethoxy)methyl or α-methoxyisopropyl.
 4. Acompound according to claim 1wherein R is ethoxymethyl, propoxymethyl,butoxymethyl, isobutoxymethyl, isopropoxymethyl, t.-butoxymethyl,amyloxymethyl, isoamyloxymethyl, α-methoxypropyl, β-methoxypropyl,α-ethoxypropyl, β-ethoxypropyl, α-propoxypropyl, β-propoxypropyl,α-isopropoxypropyl, β-isopropoxypropyl, α-methoxybutyl, β-methoxybutyl,γ-methoxybutyl, α-ethoxybutyl, β-ethoxybutyl, γ-ethoxybutyl,allyloxymethyl, crotyloxymethyl, α -allyloxypropyl, β-allyloxypropyl,α-crotyloxypropyl, β-crotyloxypropyl, benzyloxymethyl,α-benzyloxypropyl, β-benzyloxypropyl, methoxyethoxymethyl orethoxyethoxymethyl.
 5. The compound according to claim 1 which is##SPC12##or the hydrochloride salt thereof.
 6. The compound according toclaim 1 which is ##SPC13##or the hydrochloride salt thereof.
 7. Thecompound according to claim 1 which is ##SPC14##or the hydrochloridesalt thereof.
 8. The compound according to claim 1 which is ##SPC15##orthe hydrochloride salt thereof.
 9. The compound according to claim 1which is ##SPC16##or the hydrochloride salt thereof.
 10. The compoundaccording to claim 1 which is ##SPC17##or the hydrochloride saltthereof.
 11. The compound according to claim 1 which is ##SPC18##or thehydrochloride salt thereof.
 12. The compound according to claim 1 whichis ##SPC19##or the hydrochloride salt thereof.
 13. The compoundaccording to claim 1 which is ##SPC20##or the hydrochloride saltthereof.
 14. The compound according to claim 1 which is ##SPC21##or thehydrochloride salt thereof.
 15. The compound according to claim 1 whichis ##SPC22##or the hydrochloride salt thereof.
 16. The compoundaccording to claim 1 which is ##SPC23##or the hydrochloride saltthereof.
 17. The compound according to claim 1 which is ##SPC24##or thehydrochloride salt thereof.
 18. The compound according to claim 1 whichis ##SPC25##or the hydrochloride salt thereof.
 19. The compoundaccording to claim 1 which is ##SPC26##or the hydrochloride saltthereof.
 20. The compound according to claim 1 which is ##SPC27##or thehydrochloride salt thereof.
 21. The compound according to claim 1 whichis ##SPC28##or the hydrochloride salt thereof.
 22. The compoundaccording to claim 1 which is ##SPC29##or the hydrochloride saltthereof.
 23. The compound according to claim 1 which is ##SPC30##or thehydrochloride salt thereof.
 24. The compound according to claim 1 whichis ##SPC31##or the hydrochloride salt thereof.
 25. The compoundaccording to claim 1 wherein R is iso--C₃ H₇ O--CH₂ --.
 26. The compoundaccording to claim 1 wherein R is iso--C₄ H₉ O--CH₂ --.
 27. The compoundaccording to claim 1 wherein R is C₂ H₅ --CH(CH₃)--O--CH₂ --.